APPLICANT'S ABSTRACT: Ethanol's modulation of anxiety is a significant contributing factor to the abuse of this drug. For example, the punishment of withdrawal following chronic ethanol ingestion may help perpetuate abuse by the alcoholic individual. This intimate association between ethanol and anxiety is found in several species; and, the neural circuitry regulating fear and anxiety behaviors is also well conserved. Classic fear-conditional approaches have implicated the amygdala, a limbic forebrain area, as playing a pivotal role in the acquisition and expression of fear/anxiety behaviors. The amygdala is therefore a likely target for anxiety-related neuro-adaptive processes elicited by chronic ethanol abuse. Importantly, preliminary data suggests that chronic ethanol exposure causes facilitation of N-methyl-D-aspartate (NMDA) receptor function in dissociated amygdala neurons. Because amygdala NMDA receptors play an important role in fear-conditioned learning, we hypothesize that ethanol-induced adaptation in NMDA receptor function may result in an ethanol-dependent, 'chemical' conditioning of this brain region. This hypothesis will be tested by two specific aims. Specific Aim #1 will characterize the effects of chronic ethanol exposure on NMDA receptors in dissociated amygdala neurons using whole-cell patch clamp electrophysiology combined with single-cell reverse transcription/polymerase chain reaction. These studies will provide cellular and molecular insight into the mechanism of chronic ethanol-induced alterations in NMDA receptor physiology. Specific Aim #2 will determine the neurophysiologic consequences of increased NMDA-dependent synaptic plasticity within the amygdala to directly address chemical conditioning by chronic ethanol. This proposal provides a unique opportunity to examine the influences of chronic ethanol exposure on the molecular, cellular, and physiologic characteristics within the amygdala's fear/anxiety circuit. The proposed studies will also advance our knowledge of the fundamental neural mechanisms regulating ethanol abuse.